Approximately 500,000 patients per year will present to the ER experiencing acute occlusion of a coronary artery in America. The treatment of choice is to reestablish flow in the occluded artery but unfortunately this can seldom be done before there has been appreciable infarction of the left ventricle. The more contractile tissue that is lost, the worse the prognosis. Since the 1970's there has been an effort to find a practical treatment for these patients that will preserve viability in the ischemic tissue. Ischemic preconditioning (IPC) was discovered in 1986 and was the first intervention identified that unambiguously increased the heart's resistance to infarction. Since then many investigators including us have been trying to understand IPC's mechanism with the hope that that such an understanding would facilitate translation of that mechanism into clinical practice. The proposed studies concentrate on understanding events occurring in IPC hearts at reperfusion. It was recently discovered that IPC's protection is mediated in the first minutes of reperfusion following lethal ischemia. Thus patients could still be treated right up to the time that they are reperfused. Accordingly a number of interventions have been found to be protective when given at reperfusion including the adenosine agonist 5'-(N-ethylcarboxamido) adenosine (NECA). I found that NECA protected by activating the same kinases as IPC. Most recently I found that IPC, postconditioning and pharmacological preconditioning with NECA all depend on an adenosine receptor being activated at reperfusion and my preliminary data indicate that the receptor in question is the low-affinity A2b. The overall hypothesis to be tested is that the difference between an IPC and a non-IPC heart is that at reperfusion redox signaling activates PKC that then sensitizes A2b-dependent signaling pathway in the IPC heart. How this occurs and why it protects will be the focus of this renewal. PUBLIC HEALTH RELEVANCE When a patient has a heart attack some of the heart muscle that is deprived of blood flow will be killed. Because heart muscle does not regenerate the heart is permanently impaired by the lost muscle. In this grant I will study the molecular mechanisms of a phenomenon termed ischemic preconditioning which makes the heart very resistant to cell death during a heart attack. Understanding its mechanism should help us devise ways to duplicate preconditioning's protection in the coronary patient.